Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-28
2002-09-24
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S385000
Reexamination Certificate
active
06455557
ABSTRACT:
FIELD OF THE INVENTION
is invention relates to a method and composition for reducing a side effect, namely somnolence, in patients receiving tizanidine drug therapy.
BACKGROUND OF THE INVENTION
Tizanidine is pharmacologically characterized as a central-acting alpha
2
(&agr;
2
) adrenoceptor agonist which has myotonolytic activity useful in the treatment of spasticity in patients with cerebral or spinal injury, muscle spasm and pain. The imidazoline chemical structure of tizanidine is related to that of the anti-hypertensive drug clonidine and other alpha
2
-adrenergic agonists, however therapeutic indications are different between the two. Tizanidine has one-tenth to one-fiftieth ({fraction (1/50)}) of the potency of clonidine in lowering blood pressure while clonidine is ineffective in treating spastic conditions. This spectrum of activities is true of the 2-amino-imidazoline alpha
2
agonists in general where differences in the ring structures to which the amino group attaches cause marked differences in pharmacologic properties. For a general background on the alpha adrenergic receptors, see Robert R. Ruffolo, Jr., .alpha.-Adrenoreceptors: Molecular Biology, Biochemistry and Pharmacology, (Progress in Basic and Clinical Pharmacology series, Karger, 1991), wherein the basis of alpha
1
/alpha
2
subclassification, the molecular biology, signal transduction (G-protein interaction and location of the significant site for interaction and ligand binding activity away from the 3′-terminus of alpha adrenergic receptors), agonist structure-activity relationships, receptor functions, and therapeutic applications for compounds exhibiting alpha-adrenergic receptor affinity is reviewed. See also Chapleo, C. B., R. C. M. Butler, D. C. England, P. L. Myers, A. G. Roach, C. F. C. Smith, M. R. Stillings & I. F. Tulloch, “Heteroaromatic Analogues of the .alpha
2
-Adrenoreceptor Partial Agonist Clonidine”, Journal of Medicinal Chemistry, Vol. 32 (1989), pp. 1627-1630.
Anti-spastic efficacy has been demonstrated for tizanidine in placebo-controlled trials, with reduction in mean muscle tone scores of 21 to 37% versus 4 to 9% for patients receiving placebo. Maximum effects in some studies have been demonstrated to occur within 2 hours of administration. In one clinical study, improvement in muscle tone occurred in 60 to 82% of tizanidine recipients, compared with 60 to 65% of baclofen and 60 to 83% of diazepam recipients, two other anti-spastic agents. Spasm frequency and clonus were also reduced by tizanidine. Wagstaff AJ; Bryson HM Drugs (NEW ZEALAND), Adis International Limited, Auckland, New Zealand, 53 (3) p435-52 (Mar 1997). The most common adverse effects associated with therapy are dry mouth and somnolence/ drowsiness. Muscle strength, as assessed by objective means, appears not to be adversely affected by tizanidine and subjective muscle weakness is reported less often by tizanidine recipients than by those receiving baclofen or diazepam.
Tizanidine can be classified generically as an amino-imidazoline adrenergic agent. In chemical nomenclature the molecule is described as 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole and is also identified with Chemical Abstracts Registry number 51322-75-9 and in Merck Index (Eleventh Addition, Merck & Co., 1989) at monograph no. 9409. The compound may form pharmaceutically acceptable acid addition salts, and is used as the hydrochloride salt in Zanaflex®, the commercially available prescription product for treatment of spasticity in the United States. Synthesis of the compound and its myotonolytic properties are disclosed in U.S. Pat. Nos. 3,843,668 and 4,053,617 which are hereby incorporated by reference in their entireties.
Pharmacologic and electrophysiologic studies over the past 20 years have shown that tizanidine is a potent, centrally acting myotonolytic agent that principally affects spinal polysynaptic reflexes. This action arises from agonistic activity of the compound at noradrenergic alpha 2 receptors, resulting in both direct impairment of excitatory amino acid release from spinal interneurons and a concomitant inhibition of facilitatory coeruleospinal pathways. Similar alpha 2-receptor-mediated inhibition of interneuronal activity appears to underlie the additional antinociceptive and anticonvulsant activity of tizanidine reported in several species and test paradigms. Despite its structural and biochemical similarity to clonidine, the cardiovascular properties of tizanidine are mild and transitory in relation to its activity as a muscle relaxant. Smith H S; Barton A E, American Journal Of Hospice & Palliative Care (UNITED STATES), 17 (1) p50-8 (January-February 2000).
Pharmacokinetics
In studies conducted on a tablet formulation, tizanidine via oral administration was essentially completely absorbed and had a half-life of approximately 2.5 hours (coefficient of variation (CV)=33%). Following administration of tizanidine, peak plasma concentrations occurred at 1.5 hours (CV=40%) after dosing. Food increased C
max
by approximately one-third and shortened time to peak concentration by approximately 40 minutes, but the extent of tizanidine absorption was not affected. Tizanidine has linear pharmacokinetics over a dose of 1 to 20 mg. The absolute oral bioavailability of tizanidine is approximately 40% (CV=24%), due to extensive first-pass metabolism in the liver; approximately 95% of an administered dose is metabolized. Tizanidine is widely distributed throughout the body; mean steady state volume of distribution is 2.4 L/kg (CV=21%) following intravenous administration in healthy adult volunteers. Tizanidine is approximately 30% bound to plasma proteins, independent of concentration over the therapeutic range. Zanaflex® monograph, 2001 Physicians' Desk Reference® Medical Economics Company, Inc. (publisher) Montvale, N.J.
Sedation/Somnolence
In multiple dose, controlled clinical studies, 48% of patients receiving any dose of tizanidine reported sedation as an adverse event. In 10% of these cases, the sedation was rated as severe compared to <1% in the placebo treated patients. Presently, patients are warned about performing activities requiring alertness, such as driving a vehicle or operating machinery while taking tizanidine. Patients are also instructed that sedation/somnolence may be additive when Zanaflex is taken in conjunction with other drugs (baclofen, benzodiazepines) or substances (e.g. alcohol) that act as CNS depressants.
The sedating effects may interfere with everyday activity. (vide infra, summary of Power of Attention studies), and the effect appears to be dose related. In a single dose study, 92% of the patients receiving 16 mg, when asked, reported that they were drowsy during the 6 hour study. This compares to 76% of the patients on 8 mg and 35% of the patients on placebo. Patients noticed the onset of this effect 30 minutes following dosing. The effect peaked 1.5 hours following dosing. Of the patients who received a single dose of 16 mg, 51% continued to report drowsiness 6 hours following dosing compared to 13% in the patients receiving placebo or 8 mg of tizanidine.
In the multiple dose studies, the prevalence of patients with sedation peaked following the first week of titration and then remained stable for the duration of the maintenance phase of the study. Zanaflex® monograph, 2001 Physicians' Desk Reference®, Medical Economics Company, Inc. (publisher) Montvale, N.J.
There remains an unmet clinical need for a pharmaceutical composition of tizanidine or its pharmaceutically acceptable salts and a method of administering a dosage form of tizanidine to a patient to reduce somnolence, a potentially dangerous side effect which often occurs with such therapy.
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Pellegrini Cara A.
Stark Paul
Criares Theodore J.
Elan Pharmaceuticals Inc.
Finnegan Henderson Farabow Garrett & Dunner
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